tbuckley/cabot-search huggingface dataset:
Abstract A007: Modulation of HER2 as a mechanism for AR expression
Authors: Daniel K.Y. Low, Scott Wilkinson, Isaiah M. King, Shana Y. Trostel, Adam G. Sowalsky
Journal: Cancer Research (2023)

Abstract Background: Intense neoadjuvant androgen deprivation therapy (inADT) is an emerging treatment paradigm for localized high-risk prostate cancer, but in certain patients a subset of tumors will recur after surgery. In tumors with endogenously low androgen receptor (AR) activity, expression of the EGFR family protein HER2 was enriched. We sought to investigate the role of HER2 in driving the proliferation of prostate cancer under androgen-depleted environments. We hypothesized that overexpression of HER2 would decrease AR activity, while its knockdown would conversely increase AR expression beyond baseline levels. Methods: The AR-expressing 22Rv1 and LNCaP prostate cancer cell lines were cultured and plated for transfection. HER2 overexpression was achieved using an exogenous HER2 (ERBB2) plasmid, while HER2 knockdown was performed using siRNA, alongside controls for both groups. Cell lysates were collected at 24-, 48-, and 72-hour time points. Western blotting was performed to examine HER2, AR, PSA, and actin expression. Results: Western blot analysis confirmed successful overexpression and knockdown of HER2, using an exogenous HER2 plasmid and siRNA, respectively. In 22Rv1 and LNCaP cells overexpressing HER2, AR (and AR-V7 in 22Rv1 cells) levels were decreased compared to the control cells. Conversely, 22Rv1 and LNCaP cells with knockdown of HER2 exhibited elevated AR expression. Biological replicates to confirm these findings are in progress. Additional studies will also examine the impact of HER2 signaling and activity on downstream pro-proliferative pathways. Conclusions: Manipulation of HER2 expression highlights a potential role of EGFR family proteins as a mechanism for prostate cancer growth in androgen-deprived environments. Future studies will validate this finding at the RNA level using qPCR and probe downstream targets of HER2 using western blotting. These preliminary findings have implications for the treatment of advanced tumors for which inADT is not a viable option. Targeting HER2 and its downstream signaling pathways represent an intriguing mechanism to overcome resistance to androgen deprivation therapy in newly-diagnosed, treatment-naïve patients. Citation Format: Daniel K.Y. Low, Scott Wilkinson, Isaiah M. King, Shana Y. Trostel, Adam G. Sowalsky. Modulation of HER2 as a mechanism for AR expression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A007.
Abstract A068: Prostate luminal progenitors as the cell-of-origin for androgen receptor-independent prostate cancer
Authors: Chee Wai Chua
Journal: Cancer Research (2023)

Abstract In the recent years, we have witnessed the emergence of androgen receptor (AR)-independent prostate cancer (AIPC) with the clinical use of second-generation androgen deprivation therapy, namely Enzalutamide and Abiraterone. Unluckily, treatment options for the end-stage AIPC patients are mainly palliative but not curable. However, the cellular origin and mechanisms involved in the evolution of AIPCs remain unclear. Previously, we have discovered that AR is not required for the survival and maintenance of progenitor property of CA stration- R esistant N kx3.1-expressing cells (CARNs), thus highlighting the AR-independent nature of this luminal progenitor subset. Interestingly, AR-deleted CARNs demonstrate gene expression profile that is highly similar to human neuroendocrine prostate cancer (NEPC), a subtype of AIPC. Moreover, upon Pten deletion and mutated Kras activation, AR-deleted CARNs can generate tumors exhibiting focal neuroendocrine differentiation, indicating the ability of CARNs to serve as a cell-of-origin for NEPC. Based on these observations, we hypothesize that AR-independent prostate luminal progenitor subsets are capable of initiating AIPC upon oncogenic transformation, while the transformed cells represent distinct subsets in AIPC that possess cancer stem cell property. In our latest assessments, we have validated the ability of CARNs to initiate NEPC using a novel genetically-engineered mouse model of prostate cancer. Moreover, we have established tumor organoids from CARNs-initiated AIPC, which are capable of generating allografts in both immunodeficient and immunocompetent mice, implying their immune-evading capability. Lastly, we have performed small molecule library screening on the transformed CARNs-derived tumor organoids to identify effective treatment options for AIPC. Taken together, our study has provided novel insights into the cellular origin of AIPCs. Consequently, targeting these prostate luminal progenitors-initiated tumor cells as well as their molecular property may serve as novel therapeutic strategies to overcome AR independence in prostate cancer. Citation Format: Chee Wai Chua. Prostate luminal progenitors as the cell-of-origin for androgen receptor-independent prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A068.
Abstract PR013: Unlocking the proteome of metastatic prostate cancer circulating tumor cells
Authors: Justin M. Drake, Zoi Sychev, Alec Horrmann, Kaylee Judith Smith, Catalina Galeano-Garces, Ali Arafa, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Megan Ludwig, Justin Hwang, Emmanuel S. Antonarakis, Jayant Parthasarathy
Journal: Cancer Research (2023)

Abstract In recent years, liquid biopsies have emerged to provide improved insights on the current disease state of a patient, but they generally rely on a small number of protein markers from immunofluorescent staining or cell-free DNA, which provides limited information especially around drug targets. As more targeted therapies and immunotherapies enter the market, selecting the optimal drug target could improve patient outcomes drastically. One way to achieve this goal is to generate multi-omic datasets from the cancer cells in circulation, known as circulating tumor cells (CTCs). In this study, we collaborated with Astrin Biosciences and used their patented isolation technology to enrich CTCs with high purity from the blood of 15 metastatic castration resistant prostate cancer (mCRPC) patients. The enriched CTCs and a patient matched control sample consisting primarily of white blood cells were divided such that RNA and protein could be interrogated from the same patient. Label free unbiased mass spectrometry-based proteomics was used to identify the CTC-enriched proteins and marks the first time a global proteomic assessment has been performed on CTCs from cancer patients. Initial analysis identified over 1,500 peptides corresponding to greater than 500 proteins from each patients’ CTCs; including increased epithelial cell markers in the CTC-enriched sample and increased WBC markers in the control sample. Hallmarks of androgen response and detection of the androgen receptor were also identified in the CTC-enriched proteome. Overall, this study was designed to show the feasibility of obtaining large scale proteomic data from a liquid biopsy and future studies will provide more insight into the clinical utility of such data with a focus on cancer signaling mechanisms and biomarkers. Importantly, as we analyze more patients, we plan to compare the proteomic data with future RNA signatures across mCRPC patients to eventually be able to correlate them with drug response with the overall goal to improve treatment selection and patient outcomes. Citation Format: Justin M. Drake, Zoi Sychev, Alec Horrmann, Kaylee Judith Smith, Catalina Galeano-Garces, Ali Arafa, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Megan Ludwig, Justin Hwang, Emmanuel S. Antonarakis, Jayant Parthasarathy. Unlocking the proteome of metastatic prostate cancer circulating tumor cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR013.
Abstract A033: Exploring synthetic lethality of targeting miR346-unfolded protein response dependent DNA damage response mechanisms in treatment-resistant prostate cancer
Authors: Dimitrios Doultsinos, Ian Mills, Claire Fletcher
Journal: Cancer Research (2023)

Abstract Background: The Unfolded Protein Response (UPR) is a key homeostatic mechanism that is activated during endoplasmic reticulum (ER) stress caused by both intrinsic (genomic instability, metabolic demand) and extrinsic (chemo/radiotherapy, nutrient deprivation, hypoxia) factors. IRE1 is the main UPR transducer, signalling the transcription factor XBP1, and IRE1 Regulated Dependent Decay (RIDD) to resolve ER stress by controlling the expression of mRNA and miRNAs. IRE1 also regulates aspects of the DNA damage response (DDR) and IRE1-binding drugs have clinical effects as monotherapies or as adjuvants to chemotherapeutics. One miRNA involved in both the DDR and IRE1 biology is miR-346, which we have shown to cause widespread DNA damage in prostate cancer (PCa), sensitising PCa to DNA damaging drugs and associating with improved PCa outcomes. Rationale: In RNAseq data datasets we have shown that miR-346 causes a widespread transcriptional downregulation of DDR markers whilst we observed the opposite in IRE1-CRISPR-KO PCa cells. We have also developed novel IRE1 modulators that sensitise cancers to chemotherapy in vivo. These findings offer a strong rationale to explore co-targeting of miR-346 and IRE1 in the presence of DNA damaging agents to treat aggressive forms of PCa. Consequently, we want to elucidate the exact biology underpinning the miR346-IRE1/XBP1/RIDD-DDR axis to prognosticate treatment groups with gene signatures as proxies of PARPi/chemotherapeutic susceptibility. Impact: If miR-346 is a downstream effector of IRE1 activity, then an IRE1 prognostic signature can act as proxy for stratification and selection of patients for miR-346 treatment as sensitiser to DNA damaging agents whilst if miR-346 and IRE1 work in parallel, we could achieve clinically significant results by exploiting synthetic lethality. By stratifying large cohorts through IRE1/miR-346/DDR signatures (personalised precision medicine) we can increase the pool of patients for whom DNA damaging agents are effective by inducing a BRCAness phenotype, improving treatment responses and quality of life. Citation Format: Dimitrios Doultsinos, Ian Mills, Claire Fletcher. Exploring synthetic lethality of targeting miR346-unfolded protein response dependent DNA damage response mechanisms in treatment-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A033.
Abstract B033: Probing the role of hypoxia and the tumor microenvironment at spatially resolved single cell resolution in prostate cancer disease trajectories
Authors: Migle Mikutenaite, Evdoxia Karadoulama, Ronald Simon, Sarah Minner, Robert Bristow, Guido Sauter, Thorsten Schlomm, Joachim L. Weischenfeldt
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is the second most common cancer in men. Most patients will not develop aggressive disease, and a main challenge is to distinguish those patients that can be put on surveillance strategies from those that require definite treatment. Identifying robust prognostic and predictive biomarkers from tumor biopsies have been challenging due to the intra-tumor heterogeneity (ITH) and long life-history of the disease. Several components of the tumor micro-environment (TME) have been associated with shorter time to biochemical relapse and time to metastasis, but these analyses have mostly been based on single sample analysis, thus neglecting the high degree of ITH in PCa. Here, we performed pathology-guided 3D spatial sampling of PCa, followed by multi-layered genomic and transcriptomic profiling. Using single-cell sequencing from multiple distinct areas from each patient, we find both genomic, transcriptional and cellular ITH. We identify “pockets” of the tumor associated with markers of hypoxia and oxidative phosphorylation, and that these are associated with specific tumor and stromal cell-types. Using copy-number based analysis, our data reveal clonal evolution patterns at the single-cell level, pointing towards the earliest clonal populations, and our data supports an interplay between clonal evolution and tumor-promoting TMEs. Citation Format: Migle Mikutenaite, Evdoxia Karadoulama, Ronald Simon, Sarah Minner, Robert Bristow, Guido Sauter, Thorsten Schlomm, Joachim L. Weischenfeldt. Probing the role of hypoxia and the tumor microenvironment at spatially resolved single cell resolution in prostate cancer disease trajectories [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B033.
Abstract IA020: Senescence in cancer and myeloid cells control prostate cancer progression
Authors: Andrea Alimonti
Journal: Cancer Research (2023)

Abstract Recent evidence demonstrates that senescence can act as a tumor-suppressive or tumor-promoting mechanism in cancer. Here, I will discuss recent findings demonstrating that cellular senescence can promote metastases formation in prostate cancer and that therapies that eliminate senescent tumor cells (senolytics) or reprogram the SASP (senostatics) can efficiently prevent metastases in different mouse models. Moreover, I will present recent data demonstrating that senescence can occur in tumor-infiltrating myeloid cells (PMN-MDSCs). As previously reported, this population of immune cells can support prostate tumor proliferation through different mechanisms. Senescent-like myeloid cells express TREM2, are more immunosuppressive and tumor-promoting, and have an increased lifespan than canonical PMN-MDSCs. Genetic and pharmacological elimination of senescent-like myeloid cells decreases tumor progression in different mouse models of prostate cancer. These results support the development of senolytics targeting cancer and senescent-like myeloid cells for cancer therapy. Citation Format: Andrea Alimonti. Senescence in cancer and myeloid cells control prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA020.
Abstract B076: IGFBP3 promotes resistance to olaparib via modulating EGFR signaling in advanced prostate cancer
Authors: Amy R. Leslie, Allen C. Gao, Alan P. Lombard, Shu Ning
Journal: Cancer Research (2023)

Abstract Background: Castration-resistant prostate cancer (CRPC) is an incurable disease and a leading cause of cancer death in men worldwide. Olaparib (Lynparza) was among the first PARP inhibitors (PARPi) approved for the treatment of CRPC tumors harboring DNA repair defects. However, clinical resistance to PARPi’s has been documented. The mechanisms underlying resistance to PARPi’s remain elusive. To study acquired resistance, we developed olaparib-resistant LN-OlapR and 2B-OlapR cell lines generated through chronic olaparib treatment of the olaparib-sensitive cell lines LNCaP and C4-2B, respectively. RNA-seq revealed IGFBP3 is overexpressed in both OlapR cell lines. IGFBP3 overexpression is correlated with poor clinical outcome and is thought to participate in DNA repair pathways. IGFBP3 plays a key role in nonhomologous end joining (NHEJ) repair through a ternary complex with EGFR and DNA-PKcs. The IGFBP3/EGFR signaling axis is thought to modulate NHEJ repair and could have implications for PARPi sensitivity. We hypothesize that increased IGFBP3 expression promotes PARPi resistance by enhancing DNA repair capacity. Methods: RNA-sequencing and gene set enrichment analysis were used to determine the expression profile changes in resistant cells compared to parental cells. Real time PCR and western blots confirmed the expression of DNA damage repair genes such as γH2AX, EGFR, and DNA-PKcs. ELISA was used to determine IGFBP3 secretion. RNAi was used to inhibit IGFBP3 and EGFR expression. Gefitinib was used to inhibit EGFR activity. Cell viability assays were used to assess cell growth. Results: Transcriptomic profiling revealed that IGFBP3 is highly expressed in resistant models. We verified increased levels of IGFBP3 RNA and protein in both OlapR models. We found that RNAi inhibition of IGFBP3 increases γH2AX and cleaved-PARP protein levels in the resistant models, which suggests accumulation of DNA double strand breaks (DSBs) leading to genomic instability and cell death. We discovered increased phosphorylation of EGFR and DNA-PKcs in the resistant cells. Furthermore, silencing/inhibiting IGFBP3 and EGFR reduces OlapR cell viability and resensitizes resistant cells to treatment. Conclusions: Our findings demonstrated that inhibiting IGFBP3 and EGFR aids in PARPi sensitivity in the resistant setting. Future work will utilize OlapR models to study how the IGFBP3/EGFR/DNA-PKcs protein complex promotes the development of resistance. Understanding the role of IGFBP3 in PARPi resistance will enhance our ability to re-sensitize resistant CRPC to PARPi therapeutics. Citation Format: Amy R. Leslie, Allen C. Gao, Alan P. Lombard, Shu Ning. IGFBP3 promotes resistance to olaparib via modulating EGFR signaling in advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B076.
Abstract A080: Male-biased metabolic and structural muscular changes driven by testosterone flare-like conditions
Authors: John M. Fenimore, Danielle Springer, Elijah Edmonston, Kunio Nagashima, Adam Sowalsky, Howard Young
Journal: Cancer Research (2023)

Abstract Background: During the first 1 to 3 weeks of LHRH-agonist therapy for recurrent or metastatic prostate cancer, an initial increase in testosterone is associated with a condition known as "flare." Flare often is accompanied by fatigue, increases in immune infiltrate in prostate cancer and cardiovascular distress. Cardiovascular myopathies and fatigue have been associated with chronic inflammatory responses and activated cell-mediated immunity. Methods and Results: Using a model of autoimmune mice with persistent low-level expression of proinflammatory interferon gamma (IFN-g), we found fatigue and aberrant cardiovascular activity in the form of reduced ejection fraction responding to exercise in male but not female mice. This finding suggests that male hormone has a potential role for impacting cardiovascular fatigue with a more activated immune environment. Furthermore, analysis of cardiovascular tissues revealed an increase in factors associated with fatigue, such as lactic acid production and changes in expression of genes associated with an increase in anaerobic respiration and poor mitochondrial performance in cardiac musculature. Conclusion: These results indicate that the chronic expression of IFN-g may be synergetic with androgen to produce a male-biased fatigue and muscle dysfunction. Considering that the most frequent side effects to activated immune therapies to cancer in males undergoing CAR-T therapies are fatigue and cardiomyopathies we believe this insight may be beneficial to patients of other therapies as well. Understanding the biological effects of therapy driven flare may offer opportunities for physiological interventions in patients undergoing persistent or intermittent LHRHa therapy. Citation Format: John M. Fenimore, Danielle Springer, Elijah Edmonston, Kunio Nagashima, Adam Sowalsky, Howard Young. Male-biased metabolic and structural muscular changes driven by testosterone flare-like conditions [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A080.
A Tumor Microenvironment Model of Pancreatic Cancer to Elucidate Responses toward Immunotherapy (Adv. Healthcare Mater. 14/2023)
Authors: Verena Kast, Ali Nadernezhad, Dagmar Pette, Anastasiia Gabrielyan, Maximilian Fusenig, Kim C. Honselmann, Daniel E. Stange, Carsten Werner, Daniela Loessner
Journal: Advanced Healthcare Materials (2023)

3D Cancer Models In article 2201907 by Daniela Loessner and co-workers, the tumor microenvironment of pancreatic cancer is engineered using star poly(ethylene glycol) (PEG)–heparin hydrogels, that are functionalized with integrin-binding and protease-responsive peptides to stimulate cell proliferation and migration. The coculture of cancer cells and patient-derived stromal cells mimics the multicellular composition of tumor tissues and cancer–immune interactions and allows the testing of immunomodulatory treatments in combination with chemotherapy.
Abstract B056: Homoharringtonine, a translational inhibitor, induces dramatic apoptosis in prostate cancer xenografts
Authors: Akira Ohtsu, Seiji Arai, Tatsuhiro Sawada, Mai Kato, Yuta Maeno, Yoshiyuki Miyazawa, Yoshitaka Sekine, Kazuhiro Suzuki
Journal: Cancer Research (2023)

Abstract Introduction: We have previously shown that prostate cancer is primed to undergo apoptosis with BH3 mimetics targeting anti-apoptotic proteins, including BCL2, BCLXL, and MCL1 (Arai S, Balk SP et al. Clin Cancer Res 2018). We have also revealed that receptor tyrosine kinase inhibitors induced MCL1 degradation through integrated stress response and mitochondrial E3 ubiquitin ligase MARCH5 (Arai S, Balk SP et al. eLife 2020). Thus, we hypothesized that drugs targeting mitochondria might decrease MCL1 and induce apoptosis in prostate cancer. Methods: In this study, we have conducted a small-scale screening of a commercially available drug library (84 compounds) that is supposed to target mitochondria in prostate cancer cells. We have selected the top 5 drugs that could decrease prostate cancer cell growth at 1 μM levels. Results: Homoharringtonine, an FDA-approved translational inhibitor for chronic myelogenous leukemia, decreased cell growth within nM levels in multiple prostate cancer cell lines in vitro. Mechanistically, homoharringtonine rapidly reduced several proteins (MCL1, AR, AR-V7, and c-MYC) through translational inhibition and significantly induced apoptosis in prostate cancer cells in vitro. Importantly, homoharringtonine dose-dependently led to the regression of prostate cancer xenografts in vivo. Conclusions: Homoharringtonine might be a good candidate drug to treat prostate cancer. Citation Format: Akira Ohtsu, Seiji Arai, Tatsuhiro Sawada, Mai Kato, Yuta Maeno, Yoshiyuki Miyazawa, Yoshitaka Sekine, Kazuhiro Suzuki. Homoharringtonine, a translational inhibitor, induces dramatic apoptosis in prostate cancer xenografts [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B056.